rs565781501

Variant names:

• chr12-32747364-C-CT
• rs565781501
• NM_001040436.3:c.1275-2dupA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_001040436.3(YARS2):​c.1275-2dupA variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000602 in 1,613,674 control chromosomes in the GnomAD database, including 6 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: YARS2 NM_001040436.3 splice_acceptor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.11
• Publications: 3 publications found

Genes affected

YARS2 (HGNC:24249): (tyrosyl-tRNA synthetase 2) This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]

YARS2 Gene-Disease associations (from GenCC):

• myopathy, lactic acidosis, and sideroblastic anemia 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• myopathy, lactic acidosis, and sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• BP6: Variant 12-32747364-C-CT is Benign according to our data. Variant chr12-32747364-C-CT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215425.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00325 (495/152286) while in subpopulation AFR AF = 0.0111 (461/41558). AF 95% confidence interval is 0.0103. There are 4 homozygotes in GnomAd4. There are 234 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040436.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS2	NM_001040436.3	MANE Select	c.1275-2dupA		splice_acceptor intron	N/A	NP_001035526.1	Q9Y2Z4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS2	ENST00000324868.13	TSL:1 MANE Select	c.1275-2_1275-1insA		splice_acceptor intron	N/A	ENSP00000320658.8	Q9Y2Z4
	YARS2	ENST00000874023.1		c.1107-2_1107-1insA		splice_acceptor intron	N/A	ENSP00000544082.1
	YARS2	ENST00000874022.1		c.1104-2_1104-1insA		splice_acceptor intron	N/A	ENSP00000544081.1

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 497 AN: 152168 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000942 AC: 235 AN: 249590 AF XY: 0.000725

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000326 AC: 477 AN: 1461388 Hom.: 2 Cov.: 31 AF XY: 0.000309 AC XY: 225 AN XY: 727014

African (AFR) AF: 0.0110 AC: 367 AN: 33478

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5764

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111946

Other (OTH) AF: 0.000762 AC: 46 AN: 60384

GnomAD4 genome AF: 0.00325 AC: 495 AN: 152286 Hom.: 4 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74466

African (AFR) AF: 0.0111 AC: 461 AN: 41558

American (AMR) AF: 0.00150 AC: 23 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00212 Hom.: 1

Bravo AF: 0.00352

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Myopathy, lactic acidosis, and sideroblastic anemia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs565781501; hg19: chr12-32900298;